Organic Letters
Letter
a b
,
Scheme 1. Synthetic Methods of Thiazole-2-thiones
Table 1. Optimization of Reaction Conditions
entry
oxidant
solvent
T (°C) time (h) yield (%)
1
2
3
4
5
6
7
8
DCP (4 equiv)
DCP (4 equiv)
DCP (4 equiv)
DCP (4 equiv)
DCP (4 equiv)
DCP (4 equiv)
DCP (4 equiv)
DCP (4 equiv)
TBHP (4 equiv)
DTBP (4 equiv)
CHP (4 equiv)
BPO (4 equiv)
TBPB (4 equiv)
TBPB (4 equiv)
TBPB (4 equiv)
TBPB (2 equiv)
TBPB (3 equiv)
TBPB (5 equiv)
1,3-dioxolane
1,4-dioxane
acetonitrile
toluene
DMSO
DMF
130
130
130
130
130
130
130
130
130
130
130
130
130
120
140
130
130
130
12
12
12
12
12
12
12
12
12
12
12
12
3
83
55
52
23
27
36
n.r.
n.r.
n.r.
n.r.
n.r.
65
84
47
83
65
85
83
c
DCM
THF
9
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
1,3-dioxolane
10
11
12
13
14
15
16
17
18
12
3
12
3
3
a
Reaction conditions: 1a (0.5 mmol), S8 (1.5 mmol), oxidant in 2 mL
b
c
of solvent. Isolated yields. n.r.: no reaction.
(BPO) afforded a low yield (entry 12). Gratifyingly, tert-
butyl peroxybenzoate (TBPB) resulted in a sharp decrease of
the reaction time, but the yield of 2a was not affected (entry
13). When the reaction temperature was decreased to 120 °C,
a significant reduction in the yield of product 2a was observed
(entry 14). Increasing the reaction temperature did not lead to
any improvement (entry 15). Additionally, the effect of
different oxidant loading was investigated, with 3.0 equiv
found to give the best result in 85% yield (entries 16−18).
Under the optimized reaction conditions (Table 1, entry
17), various enaminone derivatives were investigated to expand
the substrate scope of the TBPB-mediated cascade cyclization,
and all results are summarized in Schemes 2−4.
Generally, when enaminones bearing N,N-dimethyl were
examined in this transformation, the desired thiazole-2-thione
products were obtained in satisfying yields (Scheme 2). A
series of N,N-dimethyl enaminones containing either electron-
donating (EDG) or electron-withdrawing (EWG) groups or
halogen on the phenyl rings were well-tolerated, (2a−2q),
though the nitro group afforded the desired product 2i in
slightly lower yield. Notably, the phenyl ring bearing free
hydrogen groups, such as OH and AcNH, also successfully
resulted in good reactivity and gave the desired products in
58−75% yields (2n−2q). Furthermore, enaminones with
sterically hindered polycyclic and conjugated moieties, such
as 2-naphthyl, 4-biphenyl, and styryl, were also compatible
with this transformation, providing the corresponding products
2r−2u in good to excellent yields. Satisfactorily, enaminones
with heteroarene moieties, such as 2-thienyl, 2-furyl, 4-pyridyl,
and 2-pyrazinyl, did not have an adverse effect on the reaction
(2v−2y). To our delight, aliphatic enaminones, including
methyl and 1-adamantyl, were successfully converted to the
desired products 2z−2a′ in excellent yield. Importantly, to
further explore the potential applicability of this method to the
multiple new bonds in enaminones still remains with
considerable challenges that lie ahead. For example, C-
(sp3)H bonds on the aliphatic amine group in the
enaminone structure could be achieved by this transformation
to construct heterocycles, through inserting a heteroatom into
the higher-electron-density double bonds of the α-carbon.14a−d
With our continued interest in enaminone chemistry and direct
transformations of C(sp3)H bonds,15 herein, we first report
a new approach for the construction of thiazole-2-thiones
through tert-butyl peroxybenzoate (TBPB)-promoted oxidative
cascade cyclization of enaminones with elemental sulfur. In this
transformation, two CS bonds and a CS bond are
efficiently formed via a sequenced C(sp2)H/C(sp3)H
bond sulfuration, cyclization, and C(sp3)H thiocarbonyla-
tion process under metal-free conditions.
We started our investigation by choosing enaminones 1a and
elemental sulfur as model substrates. To our delight, the
desired thiazole-2-thione 2a was obtained in 83% yield in the
presence of dicumyl peroxide (DCP) with 4.0 equiv in 1,3-
dioxolane at 130 °C for 12 h (Table 1, entry 1), and its
structure was unambiguously confirmed by X-ray crystallo-
graphic analysis (CCDC 2062625). Other solvents were
screened, and it was revealed that 1,4-dioxane, acetonitrile,
toluene, dimethyl sulfoxide (DMSO), and N,N-dimethylfor-
mamide (DMF) resulted in a lower yield than in 1,3-dioxolane
(entries 2−6), while dichloromethane (DCM) and tetrahy-
drofuran (THF) gave unsuccessful results (entries 7 and 8).
Next, a handful of oxidants were examined. tert-Butyl
hydroperoxide (TBHP), di-tert-butyl peroxide (DTBP), and
cumyl hydroperoxide (CHP) proved to be ineffective for this
cyclization reaction (entries 9−11). Dibenzoyl peroxide
3077
Org. Lett. 2021, 23, 3076−3082